DESCRIPTION: Incremental improvements in label free screening technologies over the past decade have not produced the capability necessary to support the changing needs of drug discovery programs. Persistent artifacts related to non-specific binding, promiscuous binding, precipitation, complex binding, tubing retention, aggregation, and sub-optimally designed platforms continue to hinder progress. Substantial progress has been made in establishing methodologies that maximize the value of the data that is currently available. The proposed platform encompasses a variety of novel adaptations including a dual mode detector exploiting surface plasmon resonance (SPR), which is sensitive to changes at the surface, and bulk solution-sensitive critical angle refractometry (CAR). Taylor dispersion-based continuous titrations (OneStepTM) and stepped analyte titrations (FastStepTM) are combined with an innovative thermal gradient capability to provide a high throughput thermodynamic screening format (DH, DS, DCp) capable of producing over 2000 isotherms/day. The realizable mass sensitivity will approach 30 fg/mm2 while the effects of mismatched buffer conditions are automatically compensated by the CAR response. Dual component titrations allow rapid compound pre-screening covering a large matrix of buffer conditions in a single run. We expect that access to these convenient optimization tools will significantly reduce artifacts and rescue many compounds that would otherwise be discarded. OneStepTM titrations will extend over 3-4 orders in concentration and provide high resolution of multisite binding events. Compound binding usually follows a rapid approach to steady state, allowing the binding curves from each titration to be treated as affinity isotherms. These time- dependent isotherms can be directly fitted with a multi-site affinity model containing dispersion terms in addition to kinetic and/or affinity binding terms for each interaction site that will return estimates of the analyte diffusio coefficient (D) along with the interaction constants (kon, koff, KD).